At the crossroads of SUMO and NF-κB

BACKGROUND: Recognition of pathogens by immune receptors leads to activation of macrophages, dendritic cells, and lymphocytes. Signals are communicated to enhance expression of target molecules such as cytokines and adhesion molecules, depending on activation of various inducible transcription factors, among which the family NF-κB transcription factors plays an evolutionarily conserved and critical role. Classical activation of NF-κB involves phosphorylation, polyubiquitination and subsequent degradation of the inhibitor molecules of NF-κB, referred to as IκB. Modification of IκBα, one of the mammalian IκB isoforms, with the small ubiquitin-like modifier (SUMO) results its protection from degradation. PRESENTATION OF THE HYPOTHESIS: SUMO-IκBα localizes in the nucleus. The nuclear SUMO-IκBα pool may be dynamic. SUMO-IκBα functions as synergy control factor. TESTING THE HYPOTHESIS: Immunoprecipitation from cellular fractions, (35)S methionine pulse-chase, and FRET assays should reveal the localization of SUMO-IκBα and the dynamics of the pool. Expression of SUMOylation defective IκBα in an IκBα (-/- )background should yield insights into the function of SUMO-IκBα. IMPLICATION OF THE HYPOTHESIS: IκBα contains the required SUMOylation motif but IκBβ does not. The suggested study would provide evidence whether or not IκBα and IκBβ can substitute each other. In addition, the suggested assays would reveal a possible redundancy in controlling transcriptional activity of NF-κB.